FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR

Abstract

Background Overexpression of fibroblast growth factor receptor 3 (FGFR3) has been linked to tumor progression in many types of cancer. The role of FGFR3 in melanoma remains unclear. In this study, we aimed to uncover the role of FGFR3 in the growth and metastasis of melanoma. Methods FGFR3 knockdown and overexpression strategies were employed to investigate the effects of FGFR3 on colony formation, cell apoptosis, proliferation, migration, and in vitro invasion, along with the growth and metastasis of melanoma in a xenografts mouse model. The protein expression levels of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), epidermal growth factor receptor (EGFR), and epithelial-mesenchymal transition (EMT) markers were determined by Western blot analysis. Results The mRNA expression of FGFR3 was higher in melanoma tissues than normal healthy tissues. FGFR3 expression in cutaneous malignant melanoma (CMM) tissues was positively correlated with the Breslow thickness and lymph node metastasis. In A357 cells, knockdown of the FGFR3 gene decreased the colony formation ability, cell proliferation, invasion, and migration, but increased the caspase 3 activity and the apoptosis rate; overexpression of FGFR3 increased the colony formation ability, cell proliferation, invasion, and migration, but decreased the caspase 3 activity and apoptosis rates. FGFR3 knockdown also upregulated E-cadherin, downregulated N-cadherin and vimentin, and decreased the phosphorylation levels of ERK, AKT, and EGFR. In the MCC xenografts mice, knockdown of FGFR3 decreased tumor growth and metastasis. Conclusions FGFR3, which is highly expressed in CMM tissues, is correlated with increased Breslow thickness and lymph node metastasis. FGFR3 promotes melanoma growth, metastasis, and EMT behaviors, likely by affecting the phosphorylation levels of ERK, AKT, and EGFR.

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

“…Demonstration of ERK-mediated EMT was also found in pancreatic and prostate cancer cell lines (109,110). Moreover, FGFR3 and WISP1 overexpression in melanoma could also promote ERK-mediated EMT (111,112). ERK1 and ERK2, together with other MAPKs JNK and p38 MAPK, were found to stabilize the phosphorylation site of TWIST1 for EMT induction in breast cancer cells (113).…”

Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

“…Wildtype cells lacking these gene alterations showed variable dependency on glucose or glutamine for sustaining growth [ 206 ]. Similar to most RTKs, FGFR3 can activate the MAPK-ERK [ 207 ] signaling pathway and the PI3K-AKT pathway [ 208 , 209 ], sustained signaling through which can influence metabolic flux by the canonical metabolic master regulators MYC and mTORC, respectively ( Figure 3 ). However, the FGF/FGFR axis exerts metabolic control beyond the regular signaling functions of a receptor tyrosine kinase.…”

Comprehensive analysis and identification of key genes and signaling pathways in the occurrence and metastasis of cutaneous melanoma

“…Meanwhile, bone morphogenetic protein (BMPs) is involved in the regulation of MMPs and is an inevitable factor in the migration and invasion of melanoma cells (Rothhammer, Braig & Bosserhoff, 2008). Fibroblast growth factor receptor 3 (FGFR3) may promote melanoma growth, metastasis, and EMT behavior by influencing the phosphorylation levels of ERK, AKT, and EGFR (Li et al, 2019a). The loss of EphB6 may have deleterious immunological effects in cancer progression, while Hafner et al (2003) found that its expression decreased gradually in N, PM and MM.…”